Protein tyrosine phosphatase 1B (PTP-1B) inhibitors and methods of using the same

Abstract

A novel class of compounds has been identified that inhibit PTP-1B through a newly discovered binding interaction. Methods of treating, preventing or delaying the onset of, conditions mediated by PTP-1B are also provided. The compounds are capable of interacting with the primary binding pocket of PTP-1B via a hydrogen bond acceptor and have an aqueous phase free energy more positive than about −1200 kJ/mol. Representative compounds in the class are those of Formula I: or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and/or R 3 are independently hydrogen atoms or alkyl groups and G 1 and G 2 are aryl, heteroaryl, alkyl, arylalkanyl, arylalkenyl, arylalkynyl, heteroarylalkanyl, heteroarylalkenyl, or heteroarylalkynyl moieties.

1 . A pharmaceutical composition of  claim 1 , wherein the compound has a formula according to Formula (I):  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2  and/or R 3  are independently hydrogen atoms or alkyl groups and G 1  and G 2  are aryl, heteroaryl, alkyl, arylalkanyl, arylalkenyl, arylalkynyl, heteroarylalkanyl, heteroarylalkenyl, or heteroarylalkynyl moieties.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound has a formula according to Formula I and G 1  and G 2  are (4-arylC 1-8 alkyl)C 1-8 alkyl.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the compound of formula I is provided in a therapeutically effective amount.  
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the compound of formula I is provided in a prophylactically effective amount.  
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the composition is adapted for administration as a part of a combination therapy.  
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the composition is adapted for combination therapy via the inclusion therein of an additional therapeutic agent.  
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the composition is adapted for combination therapy via the provision in connection therewith a description of a dosing regimen including administration of an additional pharmaceutical composition comprising an additional therapeutic agent.  
     
     
         9 . A method of treating a subject suffering from a condition mediated by PTP-1B, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a compound capable of interacting with the primary binding pocket of PTP-1B and having a formula according to Formula I:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2  and/or R 3  are independently hydrogen atoms or alkyl groups and G 1  and G 2  are aryl, heteroaryl, alkyl, arylalkanyl, arylalkenyl, arylalkynyl, heteroarylalkanyl, heteroarylalkenyl, or heteroarylalkynyl moieties.  
     
     
         10 . The method of  claim 9 , wherein G 1  and G 2  are (4-arylC 1-8 alkyl)C 1-8 alkyl.  
     
     
         11 . The method of  claim 10 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof.  
     
     
         12 . The method of  claim 9 , wherein the step of administering comprises administering a pharmaceutical composition comprising the compound of Formula I.  
     
     
         13 . The method of  claim 9 , wherein the pharmaceutical composition comprises an additional therapeutic agent.  
     
     
         14 . The method of  claim 13 , wherein the additional therapeutic agent comprises an anti-diabetes compound, anti-obesity compounds, a compound for lipid profile control, or a combination of these.  
     
     
         15 . The method of  claim 13 , wherein the additional therapeutic agent comprises an anti-cancer agent.  
     
     
         16 . A method of inhibiting in a subject the onset of a disorder related to PTP-1B, comprising administering to said subject a prophylactically effective amount of a pharmaceutical composition comprising a compound capable of interacting with the primary binding pocket of PTP-1B and wherein the compound has a formula according to Formula I:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2  and/or R 3  are independently hydrogen atoms or alkyl groups and G 1  and G 2  are aryl, heteroaryl, alkyl, arylalkanyl, arylalkenyl, arylalkynyl, heteroarylalkanyl, heteroarylalkenyl, or heteroarylalkynyl moieties.  
     
     
         17 . The method of  claim 16 , wherein G 1  and G 2  are (4-arylC 1-8 alkyl)C 1-8 alkyl.  
     
     
         18 . The method of  claim 17 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof.  
     
     
         19 . The method of  claim 16 , wherein the step of administering comprises administering a pharmaceutical composition comprising the compound of Formula I.  
     
     
         20 . The method of  claim 19 , wherein the pharmaceutical composition comprises an additional therapeutic agent.  
     
     
         21 . The method of  claim 20 , wherein the additional therapeutic agent comprises an anti-diabetes compound, anti-obesity compounds, a compound for lipid profile control, or a combination of these.  
     
     
         22 . The method of  claim 20 , wherein the additional therapeutic agent comprises an anti-cancer agent.  
     
     
         23 . The method of  claim 9 , wherein said disorder is a disorder in glucose and lipid metabolism.  
     
     
         24 . The method of  claim 9 , wherein said disorder in glucose and lipid metabolism is hypertension, type I Diabetes Mellitus, or a condition of reduced insulin sensitivity.  
     
     
         25 . The method of  claim 9 , wherein said condition of reduced insulin sensitivity is type 2 Diabetes Mellitus or obesity.  
     
     
         26 . A method of inhibiting PTP-1B comprising contacting a compound capable of interacting with the primary binding pocket of PTP-1B via a hydrogen bond acceptor and having an aqueous phase free energy more positive than about −1200 kJ/mol with a medium comprising PTP-1B, thereby causing the compound to bind with PTP-1B thereby inhibiting the activity of PTP-1B.  
     
     
         27 . The method of  claim 26 , wherein the medium comprising PTP-1B is a cell.  
     
     
         28 . The method of  claim 26 , wherein the compound has an aqueous phase free energy more positive than about −400 kJ/mol.  
     
     
         29 . The method of  claim 26 , wherein the compound has an aqueous phase free energy more positive than about −60 kJ/mol.  
     
     
         30 . The method of  claim 26 , wherein the compound has a formula according to Formula:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2  and/or R 3  are independently hydrogen atoms or alkyl groups and G 1  and G 2  are aryl heteroaryl, alkyl arylalkanyl, arylalkenyl, arylalkynyl, heteroarylalkanyl, heteroarylalkenyl, or heteroarylalkynyl moieties.  
     
     
         31 . The method of  claim 30 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug or metabolite form, or a pharmaceutically acceptable salt thereof.